Objectives: To better understand the reasons why patients default from antiretroviral treatment (ART) programmes to help design interventions that improve treatment retention and ultimately, patient outcomes. Methods: Prospective cohort study at two treatment sites in South Africa followed by qualitative interviews with patients that had defaulted. Results: Respondents overwhelmingly reported that ART improved their health status and quality of life. Nevertheless, despite improved health from taking ART and worse health when treatment is stopped, serious barriers to treatment remained: transport costs, time needed for treatment, and logistical challenges were barriers to treatment, whereas stigma around HIV/AIDS, and side effects associated with ART were less influential. Conclusion: With a better understanding of the reasons for defaulting, interventions can be designed that improve treatment retention and ultimately, patient outcomes. This study argues for realistic interventions and policy changes designed to reduce the financial and time burden of ART and to reduce logistical barriers, such as simplifying the referral and transfer process, employing patient advocates, and adopting extended and weekend clinic hours.